Deciphering the impact of circRNA-mediated autophagy on tumor therapeutic resistance: a novel perspective

Cancer therapeutic resistance remains a significant challenge in the pursuit of effective treatment strategies. Circular RNAs (circRNAs), a class of non-coding RNAs, have recently emerged as key regulators of various biological processes, including cancer progression and drug resistance. This review highlights the emerging role of circRNAs-mediated autophagy in cancer therapeutic resistance, a cellular process that plays a dual role in cancer by promoting both cell survival and death. Increasing evidence suggests that circRNAs can modulate autophagy pathways, thereby influencing the response of cancer cells to therapeutic agents. In this context, the intricate interplay between circRNAs, autophagy, and therapeutic resistance is explored. Various mechanisms are discussed through which circRNAs can impact autophagy, including direct interactions with autophagy-related genes, modulation of signaling pathways, and cross-talk with other non-coding RNAs. Furthermore, the review delves into specific examples of how circRNA-mediated autophagy regulation can contribute to resistance against chemotherapy and radiotherapy. Understanding these intricate molecular interactions provides valuable insights into potential strategies for overcoming therapeutic resistance in cancer. Exploiting circRNAs as therapeutic targets or utilizing them as diagnostic and predictive biomarkers opens new avenues for developing personalized treatment approaches. In summary, this review underscores the importance of circRNA-mediated autophagy in cancer therapeutic resistance and proposes future directions for research in this exciting and rapidly evolving field.

apoptosis, non-coding RNAs regulation, glutathione metabolism and ferroptosis [5][6][7].Unraveling the molecular mechanisms underlying the therapeutic resistance has become a focal point of cancer research, driving the quest for innovative strategies to enhance treatment efficacy.
In recent years, non-coding RNAs (ncRNAs) have emerged as crucial regulators of diverse cellular processes, with circular RNAs (circRNAs) being recognized as a class of ncRNAs with intriguing regulatory roles [8].CircRNAs are characterized by their covalently closed loop structure, rendering them resistant to RNA degradation pathways [9,10].This unique structural feature, along with their widespread presence across species and cell types, has garnered increasing attention toward understanding their functional relevance in health and disease [4,11].Of particular interest is the intricate interplay between circRNAs and autophagy, a conserved cellular degradation process that plays a pivotal role in maintaining cellular homeostasis and responding to stress [12].
Autophagy has been identified as a key player in cancer therapeutic resistance.By enabling cells to survive and adapt under adverse conditions induced by therapeutic agents, autophagy serves as a double-edged sword, both promoting cell survival and potentially contributing to treatment resistance [13][14][15][16][17][18].The modulation of autophagy pathways has thus emerged as an attractive target for circumventing therapeutic resistance and enhancing treatment outcomes.Recent studies have begun to unveil the intriguing connections between circRNAs and autophagy, suggesting a potential nexus between these two regulatory networks in the context of cancer therapeutic resistance.CircRNAs can modulate autophagy at various stages through different mechanisms, including sponging miRNAs to regulate autophagy-related genes and participating in signaling pathways involved in autophagy regulation.By elevating or inhibiting autophagy activity, circR-NAs influence the response of cancer cells to chemotherapeutic and radiation treatments, thereby impacting therapy sensitivity and resistance.For instance, elevated level of circCPM was detected in gastric cancer (GC) patients with 5-FU resistance.CircCPM functioned as a sponge to bind miR-21-3p, which indirectly augmented the expression of PRKAA2, leading to enhanced autophagic activity and resistance to 5-FU in GC [19].Moreover, circBANP was found to be up-regulated in colorectal cancer (CRC), which reduced the level of miR-338-3p, thereby inducing autophagy and contributing to X-ray resistance in CRC [20].However, the precise mechanisms of circRNA action, such as their potential role in autophagy-related protein recruitment or translation, remain largely unknown.Further study is needed to fully map circRNA functions, and investigating the roles of circRNAs in mediating autophagy in the context of cancer therapeutic resistance holds promise for deciphering new therapeutic targets and biomarkers.
This review aims to provide a comprehensive overview of the emerging role of cir-cRNA-mediated autophagy in cancer therapeutic resistance.We summarize the intricate molecular mechanisms through which circRNAs influence autophagy pathways, discuss their potential clinical implications as diagnostic markers and therapeutic targets, and highlight the opportunities for exploiting this knowledge to develop novel strategies for overcoming cancer therapeutic resistance.Through a deeper understanding of the interplay between circRNAs and autophagy, this review seeks to contribute to the advancement of personalized and effective cancer treatment approaches.

CircRNAs: structure, biogenesis, and functions
CircRNAs, a class of non-coding RNA molecules, possess a unique circular structure forming a closed loop structure where the 3ʹ and 5ʹ ends are covalently linked.This circular structure, resulting from a back-splicing event, makes circRNA resistant to degradation by exonucleases ribonuclease R (RNase R), giving them increased stability compared to linear RNAs [4].This stability enabling circRNAs to persist, accumulate, and influence cellular regulation over an extended period, potentially contributing to the dysregulation of critical signaling pathways in cancer therapeutic resistance.Furthermore, the stability of circRNAs may also impact their interactions with other molecules, such as miRNAs or proteins, which are known to be modulators of therapeutic response.
CircRNAs have diverse functions ranging from miRNA sponging and post-transcriptional regulation to potential protein encoding.Numerous studies have demonstrated the capacity of circRNAs to mediate different biological processes through several mechanisms.These mechanisms include the recruitment of proteins to specific locations [21], serving as coordinators of RNA binding proteins (RBPs) [22], initiating translation for novel proteins [23], regulating parental genes transcription [24], establishing scaffolds for enzyme-substrate interactions [25], and more broadly, acting as molecular decoys for miRNAs [19,20].CircRNAs contain multiple binding sites for specific miRNAs, allowing them to sequester these miRNAs and prevent them from targeting their intended mRNA transcripts.This sequestration prevents miRNA-mediated mRNA degradation or translational inhibition, effectively influencing the expression of various genes involved in pathways such as cell proliferation, differentiation, and apoptosis [9].
Categorized based on their origins and formation mechanisms, circRNAs play diverse roles crucial for understanding cancer and therapeutic resistance.The main types include: (1) Exon-intron circRNAs (EIcircRNAs), formed through back-splicing, comprising both exonic and intronic sequences; (2) Exonic circRNAs (EcircRNAs), derived exclusively from gene exons, are formed through back-splicing of exons during pre-mRNA splicing; (3) Intronic circRNAs (CiRNAs), originating from gene introns, formed through lariat-driven circularization; (4) Intergenic circRNAs, generated by circularization of intron-containing fragments (ICFs) with GT-AG splicing sites, such as tRNA intronic circRNAs (TricRNAs) [4,11,26].Following their formation, circRNAs exhibit diverse functions depending on their subtypes and cellular localization.For instance, exonic circRNAs, mainly in the cytoplasm, act as miRNA sponges and interact with RNA-binding proteins, influencing processes linked to cancer.In contrast, intronic cir-cRNAs, primarily in the nucleus, are thought to play roles in gene regulation, including transcription and alternative splicing (as depicted in Fig. 1).Altered expression of cir-cRNAs has been observed in different types of cancer, with specific circRNAs associated with cancer-related processes such as cell proliferation, invasion, and metastasis.CircRNAs are abundantly expressed in human tissues and body fluids, such as the brain, urine, blood, and saliva, and some have been identified as potential biomarkers for cancer diagnosis and prognosis [27].The classification and functional diversity of circRNAs underscore their significance in cancer biology and therapeutic resistance.

Overview of autophagy
Autophagy is a fundamental cellular process that plays a critical role in maintaining cellular homeostasis by recycling and degrading damaged or obsolete cellular components.It is a highly regulated and dynamic process that involves the formation of a Fig. 1 Overview of the autophagy process and regulatory mechanism.Autophagy consists of five main steps: initiation, phagophore nucleation, vesicle elongation, docking, and fusion and degradation.Autophagy is triggered by various stresses, such as hypoxia, oxidative stress, or energy nutrient deprivation.Under these conditions, the AMPK signaling is activated, which results in the dissociation of the ULK1/2 complex (comprising ULK1/2, ATG101, FIP200 and ATG13) from the mTORC1 complex (including GβL, mTOR, and Raptor), thereby promoting phagophore nucleation by the phosphorylating PI3KC3 complex (comprising Beclin1, AMBRA1, VPS15, VPS34, and ATG14L), and the production of local PtdIns3P in the omegasome.PtdIns3P then recruits PtdIns3P-binding proteins, such as WIPIs, DFCP1 and ATG9 vesicles, for phagophore expansion.Two ubiquitin-like conjugation systems are involved in vesicle elongation and autophagasome formation.In one system, the ATG12-ATG5-ATG16L complex (E3) is formed under the catalysis of ATG7 (E1-like enzyme) and ATG10 (E2-like enzyme).In the other system, cytosolic LC3-I is conjugated to phosphatidylethanolamine (PE) under the catalysis of protease ATG4, ATG3 and ATG7 to form membrane-bound LC3-PE complex (LC-II).Finally, a large group of molecules, including SNARE complex, HOPS complex, RAB GTPases and adaptors, cytoskeleton components, and related motor proteins, promote the fusion of the autophagosome and lysosome to form autolysosome, where the inner autophagosomal membrane and sequestered contents are degraded by lysosomal hydrolases and released for reutilization double-membrane vesicles called phagophore, which sequester targeted cellular components such as proteins or organelles to form autophagosome.The autophagosome then fuses with lysosomes for degradation.

Autophagy in chemoresistance
Autophagy plays a dual role in chemoresistance, exhibiting both pro-resistance and pro-sensitivity effects.On one hand, autophagy can promote cancer cell survival under stress, enhancing resistance to chemotherapy.Inhibition of autophagy can sensitize cancer cells to anti-cancer agents.Conversely, excessive autophagy can induce cytotoxicity, augmenting chemotherapy effectiveness against drug-resistant tumors [11].This duality makes autophagy a double-edged sword in cancer chemoresistance (as depicted in Fig. 3), modulated by various signaling pathways discussed below.

Autophagy in cancer radioresistance
Autophagy has a complex role in the response of cancer cells to radiation-induced stress, similar to its role in chemoresistance.While most studies suggest that autophagy induction can increase radioresistance, some experiments indicate that enhancing autophagy activity can restore radiosensitization.Various signaling pathways modulated by ionizing radiation (IR) can further influence therapy efficacy by regulating autophagy (Fig. 4).The PI3K/AKT/mTOR pathway plays a crucial role in IR-mediated autophagy regulation [61][62][63].Activation of this pathway, when inhibited by c-Jun, restrains protective autophagy, enhancing X-ray-induced cytotoxicity in nasopharynx cancer (NPC) [61].Conversely, mTOR activation can facilitate autophagic cell death, increasing γ-ray cytotoxicity in EGFR mutant non-small cell lung cancer (NSCLC) [62].Inactivation of the AKT/p70S6K pathway releases autophagy repression, promoting γ-radiation sensitivity in malignant glioma cells [63].

CircRNAs-mediated therapeutic resistance
The above content suggests that autophagy is a key cellular event, which not only participates in normal biological processes but also plays an important role in the treatment response of cancer cells.In recent years, studies have shown that circRNA can regulate different stages of autophagy through various mechanisms, thereby affecting the response of cancer cells to therapy.In addition to regulating autophagy, circRNA can also influence cancer cell treatment resistance through several other mechanisms.For example, circRNAs can regulate the expression levels of drug transport proteins, thereby altering the accumulation of drugs within cells [76,77].Additionally, circRNAs can regulate the apoptosis process of cancer cells [78][79][80][81], affect the degree of epithelialmesenchymal transition in cancer cells [82][83][84][85], modulate glycolytic metabolism [86][87][88], regulate factors related to cancer stem cell properties [89][90][91], participate in tumor angiogenesis [92][93][94], regulate cell cycle progression [95,96], influence DNA damage repair [97][98][99][100], and regulate the tumor microenvironment [101].In summary, circRNA plays an important role in cancer therapeutic resistance through multiple mechanisms, as depicted in Fig. 5.

Regulation of drug transporters
Drug efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance proteins (MRPs) play an important role in the development of therapeutic resistance in cancer.By pumping drugs out of cancer cells, these transporters decrease the intracellular accumulation of chemotherapy agents, reducing their efficacy.Certain circRNAs have been shown to regulate the expression of these efflux transporters, thereby modulating drug resistance.For instance, hsa_circ_103801 has been shown to increase cisplatin resistance in osteosarcoma cells by regulating MRP1 and P-gp [76].Addtionally, hsa_circ_0006404 and hsa_circ_0000735 modulate docetaxel resistance in ovarian cancer cells through P-gp regulation [77].Upregulation of transporters mediated by circRNAs can elevate drug efflux and contribute to resistance to chemotherapy treatments.

Influence on epithelial-mesenchymal transition (EMT)
EMT is a process where epithelial cancer cells lose their cell-cell adhesion and gain migratory and invasive properties associated with mesenchymal cells.EMT promotes cancer progression by enhancing cancer cell infiltration, migration and stemlike phenotypes, thus conferring therapeutic resistance [82].Studies have shown that circRNAs can modulate the EMT process, and thereby impact treatment sensitivity.For example, circ_0092367 and circESRP1 inhibited EMT and increased chemosensitivity by regulating miR-1206 and miR-93-5p [82,83].However, circCRIM1 and circ_0003998 were found to promote EMT and resist docetaxel and doxorubicin treatment by acting as ceRNAs [84,85].

Modulation of glycolytic metabolism
Cellular glycolysis is crucial for cancer progression and metabolism reprogramming.Glycolysis converts glucose into pyruvate to generate energy and biosynthetic intermediates to support rapid cell growth and proliferation [87].Studies have demonstrated that circFOXO3 promotes glycolysis and enhances cisplatin sensitivity in NSCLC cells by regulating the miR-543/Foxo3 axis [86].Conversely, exosomal hsa_circ_0005963 targets miR-122 to up-regulate PKM2 in CRC cells, thereby promoting glycolysis and conferring oxaliplatin resistance [87].Additionally, in DTX-resistant PC cells, EIF4A3-mediated circARHGAP29 overexpression heightens aerobic glycolysis, enhancing resistance [88].

Regulating cancer stem cells (CSCs)
CSCs are a small subset of cells that have self-renewal and tumor initiating abilities.They are thought to be responsible for tumor initiation, metastasis and resistance to therapy.CircRNAs have been shown to influence CSC properties and the stem celllike phenotype, which is associated with therapy resistance.CircCDR1, expressed in NSCLC cells with DDP resistance, promotes HOXA9 levels by competitively binding miR-641, thereby enhancing stem-like properties [89].Similarly, circ_001680 in CRC interacts with miR-340 to up-regulate BMI1 in NPC cells, inducing stemness and irinotecan tolerance [90].Moreover, circFAM73A in GC regulates the miR-490-3p/ HMGA2 axis, promoting stemness and DDP resistance [91].

Involvement in angiogenesis
Angiogenesis is the process of formation of new blood vessels.Rapid proliferation of tumors depends on sufficient blood supply from new vessel formation.Increased angiogenesis is associated with advanced diseases, metastasis and poor prognosis [92].Studies found circRNAs modulated angiogenesis and influenced resistance.CircHIPK2 in NSCLC augments VEGFA and miR-1249-3p binding, thereby promoting angiogenesis and DDP resistance [92].Conversely, circ_0010235 in PTX-resistant NSCLC suppresses angiogenesis via the miR-512-5p/FAM83F axis [93].Additionally, circ_0026123 in DDP-resistant OC promotes RAB1A by suppressing miR-543, contributing to angiogenesis [94].

Participation in cell cycle progression
Deregulated cell cycle progression allows uncontrolled growth of cancer cells.Cir-cRNAs are involved in modulating the cell cycle, which influences therapy response.CircATL2 in OC induces cell cycle arrest and initiates PTX resistance via the miR-506-3p/NFIB axis [95].Conversely, knockdown of hsa_circ_0000277 in ESCC increases the G0/G1 phase by regulating the miR-873-5p/SOX4 axis, promoting DDP resistance [96].

Impact on DNA damage repair (DDR)
DDR pathways are crucial for maintaining genomic stability.Elevated DDR is linked to resistance by allowing cancer cells to repair DNA damage caused by therapy [97].Cir-cRNAs were shown to regulate DDR genes and modulate resistance.CircMTHFD1L in pancreatic cancer up-regulates RPN6 by acting as an miR-615-3p sponge, promoting GEM resistance [97].Furthermore, exosomal circWDR62 from glioma cells induces MGMT expression through miR-132, thereby weakening TMZ efficacy [98].

Role in tumor microenvironment (TME)
TME refers to cellular and non-cellular components that surround and influence tumor cells.It includes fibroblasts, immune cells, blood vessels, extracellular matrix etc.The complex network of tumor-stromal cell interactions within the TME contributes significantly to therapeutic resistance [101].Studies illustrated that circRNAs shape the TME by regulating components like tumor-associated macrophages.CircITGB6 in OC facilitates IGF2BP2-mediated FGF9 expression and polarization of tumor-associated macrophages towards the M2 phenotype, conferring DDP resistance [101].

Regulation of autophagy process
Autophagy acts as a double-edged sword in cancer by promoting both cell survival and death [11].Dysregulated autophagy confers therapeutic resistance in cancers.Certain circRNAs were found to modulate autophagy and influence resistance by regulating autophagy-related genes or signaling pathways, such as hsa_circ_0000234 and circ_0006528 can influence cancer chemoresistance by regulating the autophagy process, which will be discussed in Sect."CircRNAs-mediated autophagy modulation and their impact on cancer therapeutic resistance".In summary, circRNAs exhibit multifaceted roles in treatment resistance, intricately sculpting drug transport, apoptosis, EMT, glycolysis, CSCs, angiogenesis, cell cycle, DDR, TME, and autophagy.Their dichotomous nature underscores the complexity of therapeutic resistance mechanisms, presenting promising avenues for targeted interventions .

CircRNAs-mediated autophagy modulation and their impact on cancer therapeutic resistance
CircRNAs can control various proteins involved in autophagy, a crucial process in tumor development.(1) In the initial stage of autophagy, circRNAs influence the PI3K/AKT/ mTOR pathway, which regulates autophagy [43].For instance, circRHOBTB3 and circ-ST3GAL6 impact this pathway in pancreatic and gastric cancer cells, respectively, leading to pro-survival autophagy [120,121].CircTMEM87A and circ_0005774 indirectly control autophagy by affecting proteins like ULK1, promoting autophagy and aiding cancer cell growth [122,123].(2) During the phagophore nucleation stage, certain cir-cRNAs influence molecules like ATG14 and Beclin1, initiating autophagy.Circ_0058058 and circCCDC66 affect these molecules in multiple myeloma and colorectal cancer cells, respectively, promoting cancer cell behavior [124,125].Hsa_circ_0006470 triggers autophagy by regulating Beclin1 in gastric cancer [126].(3) In the membrane expansion phase, circRNAs impact the ATG5-ATG12-ATG16L complex and LC3 conjugation system, crucial for autophagosome elongation.CircRNAs like hsa_circ_0001747, circMDK, and circFOXM1 influence these processes in various cancers, leading to autophagy activation and cancer progression [127][128][129].Hsa_circ_0006948 induces autophagy in osteosarcoma cells by affecting ATG7, promoting cancer development [130].(4) In the late maturation and fusion stage, circRNAs indirectly control autophagy-related proteins like STX17 and RAB10.For instance, circ_0000034 and hsa_circ_0001658 impact retinoblastoma and gastric cancer cells, respectively, enhancing autophagy and cancer cell behavior [131,132] (as shown in Fig. 6).
Besides its crucial role in cancer development, autophagy assumes a dual role in therapy-it can either sensitize cancer cells to treatment-induced death or reforce their resistance, leading to therapeutic failure and disease relapse.This duality underscores the need for precise regulation of autophagy to enhance treatment efficacy.Notably, recent research has unearthed the regulatory prowess of non-coding RNAs, particularly circRNAs, in modulating autophagic pathways, influencing various stages of autophagy in diverse types of cancer (as illustrated in Fig. 7 and summarized in Table 1).

Glioblastoma multiforme (GBM)
GBM, one of the most aggressive and malignant forms of brain cancer, poses a significant challenge in cancer treatment.TMZ is a standard chemotherapy drug used to treat GBM.However, resistance to TMZ often develops, leading to treatment failure.In this context, hsa_circ_0072309 has emerged as a crucial regulator in GBM and other cancers [133][134][135][136].Its down-regulation in GBM patients has been associated with poor prognosis.Notably, hsa_circ_0072309 sensitizes GBM cells to TMZ by targeting miR-100/p53 axis and activating autophagy-induced apoptosis, providing a potential avenue to overcome TMZ resistance in GBM treatment [137].

Colorectal cancer (CRC)
CRC is a prevalent malignancy with diverse molecular subtypes.Resistance to X-ray irradiation poses a significant challenge in CRC therapy.BANP protein, a human homolog of matrix attachment region (MAR) binding protein scaffold/matrix attachment region binding protein 1 (SMAR1), plays a crucial role in transcriptional suppression of multiple oncogenes [138].CircBANP (hsa_circ_0003098) has been identified as a key player in CRC, particularly in radiation resistance [139,140].Its up-regulation in CRC patients resistant to X-ray irradiation highlights its role in promoting autophagy.Silencing circBANP has been found to modulate miR-338-3p/ LC3B/p62 axis and deactivate autophagy, thereby enhancing the efficacy of X-rayinduced tumor suppression in CRC [20].

Gastric cancer (GC)
Gastric Cancer (GC) is characterized by its aggressive nature and resistance to various chemotherapeutic agents.Resistance to drugs like 5-Fluorouracil (5-FU) is a common challenge in GC treatment.CircCPM, CircCUL2, CircPVT1, and CircMCTP2 have emerged as key regulators influencing autophagy and chemoresistance in GC.
CircCPM is highly expressed in 5-FU-resistant GC patients, indicating poor survival outcomes.It acts as a sponge for miR-21-3p, enhancing the expression of AMPK subunit alpha 2 (PRKAA2) and promoting autophagy.This reduced apoptosis in GC cells, contributing to 5-FU tolerance [19].In addition, dysregulation of its parental gene CPM has been implicated in many types of cancer [141].
CircCUL2 (hsa_circ_0000234) acted as a tumor-suppressive and regulator to sensitize tumor cells to chemotherapeutic drugs [142][143][144], is down-regulated in GC patients' serum and tissues, and it is positively correlated with overall survival.When combined with miR-142-3p, it upregulate ROCK2, reducing autophagy in GC cells and increasing sensitivity to DDP [145].
There are two types of CircMCTP2 with distinct functions.One type, circMCTP2 (hsa_circ_0000658), facilitates bladder carcinoma progression by regulating the Fig. 7 Dysregulated circRNAs are involved in autophagy-mediated resistance to chemotherapy and radiotherapy in cancer.The majority of circRNAs act as miRNA sponges, which sequester miRNAs and prevent them from regulating their downstream mRNA targets, thereby affecting the initiation of autophagy.Only a few circRNAs directly interact with proteins to modulate autophagy miR-498/murine double minute-2 (MDM2) axis [148].The other type, circMCTP2 (hsa_circ_0000657), found at low levels in DDP-resistant GC cells, inhibits miR-99a-5p, promoting myotubularin-related protein 3 (MTMR3) expression.This downregulates LC3-II, weakens autophagy, and enhances DDP sensitivity [149].
These circRNAs, through intricate mechanisms, influence autophagy levels, enabling GC cells to survive and resist chemotherapy.Understanding their roles offers potential avenues for therapeutic interventions in GC treatment.

Renal cancer (RC)
RC is a malignancy originating in the kidneys and is a significant public health concern globally.Gemcitabine (GEM) is commonly employed in chemotherapy for RC.However, the development of resistance to GEM presents a major challenge in the treatment of this cancer.Elevated levels of hsa_circ_0035483 have been observed in human RC tissues.In RC cells treated with GEM, hsa_circ_0035483 induces the expression of cyclin B1 by suppressing miR-335.This, in turn, increases the levels of LC3B and inhibits cas-pase3 expression, thereby activating autophagy and promoting resistance to GEM [150].

Thyroid carcinoma (TC)
TC arises from the thyroid gland and is a prevalent cancer type worldwide.Cisplatin (DDP) is commonly used in TC chemotherapy.However, resistance to DDP poses a significant challenge in the effective treatment of TC.CircEIF6 (hsa_circ_0060060), a circRNA spliced from the eukaryotic initiation factor 6 (eIF6) gene, is up-regulated in DDP-treated TC cells.EIF6 plays a key role in the biosynthesis and function of ribosomes, and dysregulation of eIF6 is closely associated with the formation and development of cancers [151][152][153].In DDP-treated TC cells, circEIF6 suppresses miR-144-3p, leading to increased expression of transforming growth factor-alpha (TGF-α), elevated LC3B levels, promotion of autophagy, and consequent DDP insensitivity [154].

Breast cancer (BC)
BC is a heterogeneous disease with diverse molecular subtypes.Taxanes, such as Paclitaxel (PTX), are widely used in BC chemotherapy.However, resistance to PTX significantly hampers treatment outcomes.CircABCB10, circ_0006528, hsa_circ_0000199, and circINTS4 have been identified as critical circRNAs involved in autophagy regulation and chemoresistance in BC.Their roles in activating autophagy pathways shed light on the intricate mechanisms of drug resistance in BC, providing potential avenues for targeted therapies [155][156][157][158]. CircABCB10 (hsa_circ_0008717) has been implicated as an oncogene and a potential diagnostic and therapeutic target in various cancers [159].In PTX-resistant BC tissues and cells, up-regulated circABCB10, derived from its parental gene ABCB10, interacts with let-7a-5p.This interaction increases the level of dual specificity phosphatase 7 (DUSP7), enhances LC3B-mediated autophagy, and leads to PTX resistance [155].

Non-small cell lung cancer (NSCLC)
NSCLC is the most common type of lung cancer.Platinum-based drugs, such as DDP, are frequently used in NSCLC chemotherapy.However, resistance to DDP poses a significant challenge in NSCLC treatment.Hsa_circ_0085131 and circRNA_100565 have been identified as key circRNAs in DDP resistance in NSCLC.Their roles in inducing autophagy shed light on the molecular mechanisms underlying DDP resistance, offering potential targets for overcoming resistance in NSCLC therapy [165][166][167].

Cervical cancer (CC)
CC originates in the cells lining the cervix.Resistance to DDP is a common issue in CC treatment.Hsa_circ_0023404 and circMTO1 have been identified as crucial players in DDP resistance in CC.Their roles in modulating autophagy provide valuable insights into the mechanisms underlying chemoresistance in CC, paving the way for targeted interventions [173][174][175][176][177].
CircMTO1 (hsa_circ_0007874) is derived from circularized exons 2-3 of mitochondrial tRNA translation optimization 1 (MTO1) gene and plays a dual role as a carcinogenic driver or tumor suppressor in cancer [175,176].Its up-regulation in CC patients indirectly triggers autophagy by sponging miR-6893, inhibiting apoptosis, and leading to DDP resistance [177].

Laryngocarcinoma
Laryngocarcinoma, also known as laryngeal cancer, originates in the larynx.Resistance to DDP is also a significant concern in laryngocarcinoma treatment.CircPGAM1 and circPARD3 have been identified as key circRNAs influencing autophagy and DDP resistance in laryngocarcinoma.Understanding their roles in autophagy regulation provides crucial information for developing targeted therapies to overcome DDP resistance in laryngocarcinoma patients [181][182][183].
CircPARD3, formed by circularization of exon 16-22 of the human PARD3 gene, plays a dual role in cancer development and metastasis [182].In laryngeal squamous cell carcinoma patients, elevated circPARD3 levels inhibit autophagy and are associated with malignant progression and poor prognosis.CircPARD3 acts as a molecular sponge for miR-145-5p, enhancing protein kinase C-iota (PRKCI) expression.PRKCI stimulates the AKT/mTOR pathway, reducing autophagy and causing DDP resistance in laryngeal squamous cell carcinoma [183].

Oral squamous cell carcinoma (OSCC)
OSCC is a prevalent type of oral cancer.Resistance to DDP limits its efficacy in OSCC treatment.CircPKD2 (hsa_circ_0070401), a crucial circRNA derived from the polycystic kidney disease 2 (PKD2) gene, plays a significant role in influencing autophagy and DDP resistance in OSCC.It regulates OSCC proliferation, invasion, and metastasis by modulating the miR-204-3p/adenomatous polyposis coli 2 (APC2) axis [185].Recently, researchers found that increased circPKD2 levels sequester miR-646, enhancing ATG13 expression.This augmentation of autophagy alleviates DDP resistance in OSCC cells, indicating a promising strategy for overcoming drug resistance in OSCC treatment [186].Unraveling its role in autophagy regulation provides valuable insights into the mechanisms of DDP resistance, offering potential avenues for therapeutic interventions.

Prostate cancer (PC)
PC, originating in the prostate gland, is a prevalent cancer in men.Resistance to X-ray therapy poses a significant challenge in its treatment.CircCCNB2, a key circRNA, has been identified for its role in promoting autophagy and X-ray resistance in PC.Cyclin B2 (CCNB2) serves as a diagnostic and prognostic marker in various human tumors, including HCC [187], rhabdomyosarcoma [188], TNBC [189], and low-grade glioma [190].CircCCNB2, derived from CCNB2 genomic DNA, is up-regulated in PC patients resistant to radiotherapy.It absorbs miR-30b-5p, elevating KIF18A levels in PC cells.This elevation promotes LC3B and Beclin1 expression, enhancing autophagy activity and leading to X-ray resistance [191].Understanding its role in autophagy modulation provides essential insights for overcoming X-ray resistance in PC therapy.

Clinical implications and biomarker potential
The emerging understanding of circRNAs in modulating autophagy has profound clinical implications, particularly in the context of cancer therapeutic resistance.The complex roles of circRNAs in regulating autophagy pathways across diverse cancer types not only shed light on the underlying molecular mechanisms but also present promising avenues for clinical interventions and biomarker development.

Predictive biomarkers for therapeutic response
Identification of specific circRNAs associated with autophagy dysregulation provides an opportunity to develop predictive biomarkers for therapeutic response.CircR-NAs such as hsa_circ_0072309 in glioblastoma [137] and circABCB10 in breast cancer [155] exhibit clear correlations with drug sensitivity, suggesting their potential as predictive markers for treatment outcomes.Monitoring the expression levels of these circRNAs could guide clinicians in tailoring therapies based on individual patient profiles, maximizing treatment efficacy.

Overcoming chemoresistance through targeted circRNA interventions
Targeting dysregulated circRNAs involved in autophagy presents a novel therapeutic approach.Designing small molecules, antisense oligonucleotides, or CRISPR/Cas9based strategies to modulate circRNA expression could help sensitize cancer cells to conventional treatments.For instance, silencing circBANP enhances the effects of X-ray irradiation in colorectal cancer [20], while inhibiting circINTS4 sensitizes triple-negative breast cancer cells to anthracyclines [158].These targeted interventions have the potential to reverse chemoresistance and improve patient outcomes.

Monitoring treatment response and disease progression
Dynamic changes in circRNA expression patterns during treatment could serve as real-time indicators of treatment response and disease progression.Longitudinal monitoring of circRNA profiles, especially those linked to autophagy, might provide valuable insights into treatment efficacy.For example, studies have shown that circCPM enhances 5-FU resistance in gastric cancer by promoting autophagy flux [19], and circ_0006528 activates autophagy and increases paclitaxel resistance in breast cancer by interacting with miR-1299 [156].Therefore, increased expression of autophagy-promoting circRNAs like circCPM and circ_0006528 could indicate treatment resistance, prompting clinicians to consider alternative therapeutic strategies or combination therapies.

Non-invasive liquid biopsy biomarkers
CircRNAs have shown stability in body fluids, making them ideal candidates for noninvasive liquid biopsy biomarkers.Circulating circRNAs associated with autophagy dysregulation could be detected in blood, serum, or saliva samples.For example, studies have shown that exosomal hsa_circ_103801 and circWDR62 can be detected in serum and serve as non-invasive biomarkers for osteosarcoma/glioma diagnosis and prognosis prediction [76,98].Profiling these circRNAs in liquid biopsies might offer a minimally invasive method for diagnosing cancer, predicting therapeutic responses, and monitoring disease recurrence or progression [192].

Personalized autophagy-targeted therapies
Understanding the circRNA-mediated autophagy networks in individual patients could pave the way for personalized autophagy-targeted therapies.For example, elevated levels of circABCB10 and circ_0006528 in breast cancer patients may suggest that these tumors rely on autophagy activation for survival [155,156].By analyzing the specific circRNA signatures like circABCB10 and circ_0006528 in a patient's tumor, clinicians can tailor treatments to modulate autophagy pathways effectively.This personalized approach holds the potential to enhance treatment responses to paclitaxel and mitigate resistance by blocking circABCB10/ let-7a-5p or circ_0006528/ miR-1299 axes, leading to more effective cancer therapies.
In conclusion, the emerging role of circRNAs in mediating autophagy in cancer therapeutic resistance offers promising avenues for clinical applications.From predictive biomarkers and targeted interventions to non-invasive liquid biopsy markers and personalized therapies, circRNAs have the potential to revolutionize cancer treatment strategies.Continued research and clinical trials focused on circRNA-mediated autophagy regulation are essential to translate these findings into meaningful advancements in cancer patient care.

Conclusions and perspectives
The burgeoning field of circRNA-mediated autophagy regulation in cancer therapeutic resistance has illuminated novel avenues for understanding the molecular intricacies of drug resistance and has spurred the development of innovative therapeutic strategies.This review summarized the impact and potential mechanisms of circRNAs and autophagy in modulating the resistance of cancer cells to therapy, which provided evident that the complex interplay between circRNAs and autophagy pathways significantly impacts cancer treatment outcomes.The insights gained from studying circRNA-mediated autophagy modulation provide a solid foundation for future research endeavors and therapeutic interventions.
While progress has been made, the complete landscape of circRNAs involved in autophagy regulation remains largely unexplored.Future research should focus on comprehensive profiling of circRNAs across diverse cancer types and stages to identify novel circRNAs and elucidate their roles in autophagy, unveiling new therapeutic targets and biomarkers for predicting treatment responses.
Targeting the unique back-splice sites of aberrant oncogenic circRNAs using antisense oligonucleotides such as siRNA (small interfering RNA) and shRNA (short hairpin RNA), along with CRISPR/Cas13 technology, presents an opportunity to advance cancer treatment [193].In addition, utilizing tRNA splicing and plasmids containing complementary sequences and specific RBP-binding motifs in the flanking introns to increase the levels of circRNAs with tumor suppressor functions show promise for enhancing their anti-tumor effects [20].However, ensuring the specificity of circRNA-targeted therapies while minimizing off-target effects is a major challenge, highlighting the need for precise delivery systems that target cancer cells while sparing normal tissue.
Given the conflicting roles of autophagy and circRNA in tumorigenesis, personalized approaches tailored to the circRNA profile of individual patients are essentail.Furthermore, expanding our understanding of circRNA-mediated autophagy regulation beyond the ceRNA mechanism to include other regulatory modes, such as the regulation of RNA modification or translation of new proteins, is crucial for uncovering the precise role of circRNAs in the autophagy pathway [194].
Validating the clinical relevance of autophagy-related circRNAs through largescale clinical studies and rigorous validation of circRNA-based biomarkers in diverse patient populations is imperative for their widespread adoption in clinical settings.Moreover, integrating different omics data and employing new technologies such as whole-genome screening and single-cell sequencing will provide a more comprehensive understanding of circRNA-mediated autophagy regulation and its impact on cancer treatment resistance.
In conclusion, the emerging field of circRNA-mediated autophagy presents exciting opportunities for cancer therapy.Addressing research gaps and overcoming associated challenges will pave the way for the development of targeted, personalized, and effective therapies, ultimately improving the outcomes and quality of life for cancer patients.Continued interdisciplinary research efforts, collaborative initiatives, and innovative technological advancements are critical to realize the full potential of cir-cRNA-mediated autophagy regulation in cancer therapy.

Fig. 4
Fig. 4 Biogenesis and functions of circRNAs.(1) CircRNAs are primarily generated by back-splicing of pre-mRNA in the nucleus.Long flanking introns complementary sequences (such as inverted repeat elements Alu pairs) and trans acting RNA binding proteins (RBPs) participate in back-splicing to form the circular structures.CircRNAs can also be produced by lariat-intron intermediate.The cyclization of lariat is driven by GU-rich element at the upstream splicing site and C-rich element near the downstream branching point, or AG-GU motifs at both ends.In addition, circRNAs can be generated during the process of pre-tRNA sequence splicing to maturation.Furthermore, a new class of circRNAs can be formed by the cyclization of two intron-containing fragments (ICFs), with GT-AG splicing signals on both sides.(2) There are five types of circRNAs, including (a) EIcircRNA, (b) EcircRNA, (c) CiRNA, (d) TricRNAs and (e) Intergenic circRNAs.(3) It has been reported that circRNAs possess a variety of regulatory functions, such as (A) protein scaffolding, (B) miRNA sponging, (C) regulation of parental gene, (D) protein sponging, (E) protein translation and (F) protein recruitment

Fig. 6
Fig.6 CircRNAs regulate autophagy and affect cancer development.The autophagy process can be modulated by circRNAs at various stages, leading to either suppression or promotion of cancer.This schematic diagram illustrates some representative circRNAs, including circRHOBTB3, circCCDC66, circFOXM1, circ_0000034 and others, that impact cancer progression by regulating autophagy

Table 1
The roles of autophagy associated-circRNAs in chemo-and radio-therapy of malignant tumors